Age-related macular degeneration (AMD) causes progressive impairment of central vision and is the leading cause of irreversible vision loss in older Americans (1). The most severe form of AMD involves neovascular/exudative (wet) and/or atrophic (dry) changes to the macula. Although the etiology of AMD remains largely unknown, implicated risk factors include age, ethnicity, smoking, hypertension, obesity and diet (2). Familial aggregation (3), twin studies (4), and segregation analysis (5) suggest that there is also a significant genetic contribution to the disease. The candidate gene approach, which focuses on testing biologically relevant candidates, has implicated variants in the ABCA4, FBLN6, and APOE genes as risk factors for AMD. Replication of the ABCA4 and FBLN6 findings has been difficult, and in toto these variants explain only a small proportion of AMD (6-8). An alternative genomic approach uses a combination of genetic linkage and association to identify novel genes involved in AMD. We participated in a recent collaborative genome-wide linkage screen (9) in which chromosome 1q32 was identified as a likely region for an AMD risk gene, a location also supported by other studies (10, 11). This region contains between over 100 genes, (see On-line Mendelian Inheritance in Man at the NCBI website) and no particular gene was identified by this work.
Age-related macular degeneration (AMD) is a common complex disorder that affects the central region of the retina (macula) and is the leading cause of legal blindness in older American adults. The prevalence of AMD and its significant morbidity will rise sharply as the population ages. AMD is a clinically heterogeneous disorder with a poorly understood etiology. Population-based longitudinal studies (Klayer et al. 2001; van Leeuwen et al. 2003; Klein et al. 2003) have established that the presence of extracellular protein/lipid deposits (drusen) between the basal lamina of the retinal pigment epithelium (RPE) and the inner layer of Bruchs' membrane is associated with an increased risk of progressing to an advanced form of AMD, either geographic atrophy or exudative disease. The presence of large and indistinct (soft) drusen coupled with RPE abnormalities is considered an early form of the disorder and is often referred to as age-related maculopathy (ARM).
Epidemiologically, AMD is a complex disorder with contributions of environmental factors as well as genetic susceptibility (Klein et al. 2004). Many environmental and lifestyle factors have been postulated, but by far the most consistently implicated non-genetic risk factor for AMD is cigarette smoking (Smith et al. 2001). Much progress has recently been made in identifying and characterizing the genetic basis of AMD. In a remarkable example of the convergence of methods for disease gene discovery, multiple independent research efforts identified the Y402H variant in the complement factor H(CFH [(MIM 134370]) gene on chromosome 1q32 as the first major AMD susceptibility allele (Haines et al. 2005; Hageman et al. 2005; Klein et al. 2005; Edwards et al. 2005; Zareparsi et al. 2005; Conley et al. 2005). While one of the studies was able to pinpoint CFH on the basis of a whole-genome association study (Klein et al. 2005), most studies focused on the 1q32 region because it had consistently been implicated by several whole-genome linkage scans. A second genomic region with similarly consistent linkage evidence is chromosome 10q26, which was identified as the single most promising region by a recent meta-analysis of published linkage screens (Fisher et al. 2005).
Two recent studies have suggested specific AMD susceptibility genes located on chromosome 10q26. One used a combination of family-based and case-control analyses to implicate the PLEKHA1 gene (pleckstrin homology domain containing, family A (phosphoinositide binding specific) member 1 [MIM 607772]) and the predicted LOC387715 gene (Jakobsdottir et al. 2005). However, the association signals for single-nucleotide polymorphisms (SNPs) in these two genes were statistically indistinguishable. A second study using two independent case-control datasets concluded that the T allele of SNP rs10490924 in LOC387715, a coding change (Ala69Ser) in exon 1 of this poorly characterized gene, was the most likely AMD susceptibility allele (Rivera et al. 2005). Both studies reported that the chromosome 10q26 variant confers an AMD risk similar in magnitude to that of the Y402H variant in CFH. Here, we describe highly significant association of SNPs in LOC387715 with AMD. In our data, only SNPs in this gene, including rs10490924, explain the strong linkage and association signal in this region. Given a previous report of an effect of cigarette smoking on the linkage evidence in the 10q26 region (Weeks et al. 2004; 9), we tested whether smoking modified this association.
There is a continuing need in the art to identify individual genes that are involved in the pathogenesis of AMD and/or to identify particular alleles that are involved in the pathogenesis of AMD, as well as to identify the interaction of the genes with modifiable behaviors.